The synthetic pyrethroids are potent insecticides that are derivatives of natural pyrethrin-based insecticides. In rodents symptoms consisting of hyperactivity and tremors are produced by these compounds which at high doses can progress to seizures. In addition, those pyrethroids such as deltamethrine containing an Alpha-cyano substituent also produce profuse salivation and choreoathtoid movements. In preliminary studies, we have found that the neurotoxic effects of the pyrethroids are central in origin and are potentiated by agents affecting several neurotransmitter systems. In addition, there was potentiation by the excitotoxic agent kainic acid. We also found that the pyrethroids decreased the binding of 3H-kainate in the mouse brain. Low doses of the pyrethroids also decreased operant responding for food reinforcement in rats. Based on these preliminary observations, we propose to test two hypotheses. (1) That pyrethroids exert their effects by acting at receptors for excitory amino acid neurotransmitters or their analogs and (2) that effects of low doses of the pyrethroids are detectable using operant conditioning techniques. In order to accomplish these goals we propose to study the effects of pyrethroids both in vitro and in vivo on the binding of 3H-kainic acid and 3H-glutamate to rat brain membranes. In addition, we will also examine the effects of chronic treatment with these compounds on binding of the two ligands. Since trout are more sensitive to the effects of the pyrethroids than are mammals, we will compare the effects on receptor binding in trout brain to that in mammal brain. The effects of the low doses (less than 10% of the LD50) of the pyrethroids on operant responding will be examined using two paradigms. Studies will be conducted using a variable interval schedule of food reinforcement and intracranial self-stimulations as reinforcers. The synthetic pyrethroid insecticides promise to be of significant agricultural importance in the future and thus their presence in the environment will increase greatly. It is intended that the proposed studies will enable us to better understand the mechanisms by which these compounds exert their neurotoxic effects and help in ascertaining the lower dose limits of their toxicity.